H.sub.3 receptor sites are known and are of current interest to those skilled in the art--for example, see: West, Jr. et al., "Biexponential Kinetics of (R)-.alpha.-[.sup.3 H]Methylhistamine Binding to the Rat Brain H.sub.3 Histamine Receptor", Journal of Neurochemistry, Vol. 55, No. 5, pp. 1612-1616, 1990; West, Jr. et al., "Identification of Two H.sub.3 -Histamine Receptor Subtypes", Molecular Pharmacology, 38:610-613; and Korte et al., "Characterization and Tissue Distribution of H.sub.3 Histamine Receptors in Guinea Pigs by N.sup..alpha. -Methylhistamine", Biochemical and Biophysical Research Communications, Vol. 168, No. 3, pp. 979-986.
Arrang et al. in U.S. Pat. No. 4,767, 778 (Issued Aug. 30, 1988) disclose a pharmaceutical composition containing a histamine derivative of the formula: ##STR2## wherein each of R.sub.1, R.sub.2, and R.sub.4, represents a hydrogen or a methyl, or R, and R.sub.2 taken together represent a methylene, and R.sub.3 is a hydrogen, a methyl or a carboxy, with the proviso that R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are not simultaneously methyl groups. It is disclosed that the derivatives behave as complete agonists of the H.sub.3 receptors in rat brain and produce a maximal inhibition of release identical to that induced by histamine (approximately 60%). It is also disclosed that the histamine derivatives powerfully inhibit the release and synthesis of histamine by very selectively stimulating the H.sub.3 receptors. Consequently, according to Arrang et al., the derivatives are likely to decrease histaminergic transmission in the digestive tract and in the nervous, cardiovascular and immune systems. Arrang et al. disclose that the derivatives can be used in therapy as a drug having sedative effects, as a sleep regulator, anticonvulsant, regulator of hypothalmic-hypophyseal secretion, antidepressant, and modulator of cerebral circulation. According to Arrang et al., inhibition of the release of inflammation messengers in various allergic conditions (e.g., asthma) is expected to result from stimulation of the H.sub.3 receptors of the lung. It is further disclosed that the inhibition of release of gastric histamine is likely to exert antisecretory and anti ulcerative effects. According to Arrang et al., modification of release of the messengers of immune responses is likely to modulate the latter responses.
Derwent abstract 86-273706/42 for EP 0 197 840 discloses imidazole derivatives of the formula: ##STR3## wherein R.sub.1 is H, methyl or ethyl; R is H or R.sub.2 ; and R.sub.2 is 1-6C alkyl, piperonyl, 3-(benzimidazolon-1-yl)propyl, --CZ--NHR.sub.5 or a group (i): ##STR4## wherein n is 0-3; X is a bond, O, S, NH, CO, CH.dbd.CH or a group (ii): ##STR5## R.sub.3 is H, methyl, halo, CN, CF.sub.3 or COR.sub.4 ; R.sub.4 is 1-6C alkyl, 3-6C cycloalkyl or phenyl (optionally substituted by methyl or F); Z is O, S, NH, N-methyl or N--CN; and R.sub.5 is 1-8C alkyl, 3-6C cycloalkyl (optionally substituted by phenyl), 3-6C cycloalkyl(1-3C)alkyl, phenyl (optionally substituted by methyl, halo or CF.sub.3), phenyl(1-3C)alkyl, naphthyl, adamantyl or p-toluenesulphonyl. It is disclosed that these compounds are psychotropic agents. It is also disclosed that these compounds antagonize the histamine H3 receptors and increase the speed of cerebral histamine renewal.
Derwent abstract 90-184730/24 for U.S. Pat. No. 4,925,851 discloses 2- or 4-(2-(1H-imidazol-1-yl)ethyl) piperidine compounds useful as antitumour agents for inhibiting lymphoma, sarcoma, myeloma and leukemia. The compounds have the formula: ##STR6## wherein R is --CH.sub.2 (CH.sub.2).sub.m --Me, --CO--(CH.sub.2).sub.m --Me or --CO--CMe.sub.2 --R.sub.2 ; m is 2-18; R.sub.2 is H or Me; R.sub.1 is --(CH.sub.2).sub.n --R.sub.3 ; n is 0-13; R.sub.3 is H, i-Pr or t-Bu; and the floating group is at the 2- or 4-position; with the proviso that (1) the sum of C atoms in R.sub.1 does not exceed 13; and (2) the sum of C atoms in R and R.sub.1 does not exceed 25.
WO 93/12107 published Jun. 24, 1993 discloses a compound of the formula: ##STR7## or a pharmaceutically acceptable salt or solvate thereof, wherein: (A) m is an integer selected from the group consisting of: 1 and 2;
(B) n and p are integers and are each independently selected from the group consisting of: 0,1, 2, 3, and 4 such that the sum of n and p is 4 and T is a 6-membered ring; PA1 C) R.sup.3 and R.sup.4 are each independently bound to the same or different carbon atom of ring T such that there is only one R.sup.3 group and one R.sup.4 group in ring T, and each R.sup.1, R.sup.2, R.sup.3, and R.sup.4 is independently selected from the group consisting of: PA1 (D) R.sup.5 is selected from the group consisting of: PA1 (E) R.sup.7 and R.sup.8 are each independently selected from the group consisting of: H, C.sub.1 to C.sub.6 alkyl, and C.sub.3 to C.sub.6 cycloalkyl; PA1 (F) the dotted line (.dbd.) represents a double bond that is optionally present when m is 1, and n is not 0, and p is not 0, and when said double bond is present then R.sup.2 is absent; and PA1 (G) when m is 2, each R.sup.1 is the same or different substituent for each m, and each R.sup.2 is the same or different substituent for each m, and at least two of the substituents R.sup.1 and/or R.sup.2 are H. PA1 n is 0,1 or 2, PA1 m and p are 0 to 4; PA1 when m is 0 to 4, Y represents --SO.sub.2 --; --CS--; --CO--; --CONR.sup.5 --; --CO(CH.sub.2 ).sub.w O-- (with w being 1 to 4); --COO--; --CON(OR.sup.5)--; --C(NR.sup.5)NR.sup.5 --; --SO.sub.2 NR.sup.5 -- or --CSNR.sup.5 --; PA1 when m is 2 to 4, Y represents all the groups above when m is 0 to 4 and, in addition, Y represents --CHOR.sup.5 --; --O--; --NR.sup.5 CONR.sup.5 --; --NR.sup.5 CO--; --NR.sup.5 --; --OCONR.sup.5 --; --NR.sup.5 C(NR.sup.5)NR.sup.5 --; --NR.sup.5 CSNR.sup.5 ; --NR.sup.5 CS-- or --NR.sup.5 SO.sub.2 --; --NR.sup.5 C(O)O--; or --CSNR.sup.5 --; PA1 each R.sup.5 independently represents hydrogen, alkyl or benzyl; PA1 R.sup.6 represents aryl, heteroaryl, or a 3- to 7-membered heterocyclic group having one to three heteroatoms in the ring, wherein the heteroatoms are selected from N, S and O, and wherein said R.sup.6 group is optionally substituted by one to three substituents as defined below; PA1 when Y is --SO.sub.2 --, then R.sup.6, in addition to the above groups, also represents alkyl having 1 to 7 carbon atoms or a group --NR.sup.10 R.sup.11 wherein R.sup.10 and R.sup.11 are independently selected from H, alkyl or trihalomethyl; PA1 each R.sup.1 is independently hydrogen, alkyl or trihalomethyl; PA1 each R.sup.7 is independently selected from hydrogen, alkyl, trihalomethyl, phenyl or benzyl, , wherein said phenyl and benzyl are optionally substituted by one to three substituents independently selected from of alkyl, halogen, trihalomethyl, CN, NO.sub.2, OR.sup.10 or NR.sup.10 R.sup.11, wherein R.sup.10 and R.sup.11 are as above defined. PA1 alkyl--represents a straight or branched, saturated hydrocarbon chain having from 1 to 6 carbon atoms; PA1 lower alkyl (including the alkyl portions of lower alkoxy)--represents a straight or branched, saturated hydrocarbon chain having from 1 to 6 carbon atoms, preferably from 1 to 4; PA1 cycloalkyl--represents a saturated carbocyclic ring having from 3 to 6 carbon atoms, optionally substituted by 1 to 3 groups independently selected from the group consisting of lower alkyl, trihalomethyl and NR.sup.10 R.sup.11, wherein R.sup.10 and R.sup.11 as defined above; PA1 halogen (halo)--represents fluoro, chloro, bromo or iodo; PA1 aryl--represents a carbocyclic group having from 6 to 14 carbon atoms and having at least one benzenoid ring, with all available substitutable aromatic carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted with 1 to 3 groups, each independently selected from halo, alkyl, hydroxy, phenoxy, amino, loweralkylamino, diloweralkylamino, (e.g., NR.sup.10 R.sup.11 wherein R.sup.10 and R.sup.11 are independently selected from hydrogen, lower alkyl or trihalomethyl), loweralkoxy, polyhaloloweralkoxy, (e.g., OR.sup.10 wherein R.sup.10 is as above defined) polyhaloloweralkyl (e.g., trihalomethyl), CN, or NO.sub.2 ; preferred aryl groups include 1-naphthyl, 2-naphthyl and indanyl, and especially phenyl and substituted phenyl; PA1 heterocyclic--represents saturated and unsaturated non-aromatic cyclic organic groups having at least one O, S and/or N atom interrupting a carbocyclic ring structure that consists of one ring or two fused rings, wherein each ring is 3 to 7 membered (e.g., 5-, 6- or 7-membered), which ring structure has from 2 to 8, preferably from 3 to 6 carbon atoms; e.g., 2- or 3-pyrrolidinyl, 2-, 3- or 4-piperidinyl, 2- or 3-piperazinyl, 2- or 3-morpholinyl, or 2- or 3-thiomorpholinyl; said heterocyclic group being optionally substituted by 1 to 3 groups independently selected from alkyl, trihalomethyl and NR.sup.10 R.sup.11, wherein R.sup.10 and R.sup.11 are independently selected from hydrogen, alkyl or trihalomethyl, said substituents being bound to carbon atoms (substitutable carbon atoms) in the ring such that the total number of substituents in the ring is 1 to 3; and wherein said heterocyclic ring contains nitrogen atoms, said nitrogen atoms (i.e., the substitutable nitrogen atoms) being optionally substituted with lower alkyl (e.g., methyl), e.g., N-methylpyrrolidinyl; PA1 heteroaryl--represents a cyclic organic group having at least one O, S and/or N atom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic group having from 2 to 14, preferably 4 or 5 carbon atoms, e.g., 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2- or 4-imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, or 3- or 4-pyridazinyl, etc.; preferred heteroaryl groups are 2-, 3- and 4-pyridyl; said heteroaryl groups being optionally substituted with 1 to 3 groups, each optional substituent being independently selected from alkyl, halogen, trihalomethyl, CN, NO.sub.2, OR.sup.10 or NR.sup.10 R.sup.11, wherein R.sup.10 and R.sup.11 are independently selected from hydrogen, alkyl or trihalomethyl, said substituents being bound to carbon atoms (substitutable carbon atoms) in the ring such that the total number of substituents in the ring is 1 to 3; PA1 DMF--stands for N,N,-dimethylformamide; PA1 SEM--stands for 2-(trimethylsilyl)ethoxymethyl; PA1 THF--stands for tetrahydrofuran; PA1 DMAP--stands for dimethylaminopyridine; PA1 DIPA--stands for diisopropylamine; PA1 DMSO--stands for dimethyl sulfoxide; PA1 DBU--stands for diazabicycloundecene; PA1 DBN--stands for diazabicyclononane; PA1 LAH--stands for lithium aluminum hydride; PA1 FAB--stands for fast atom bombardment; PA1 CI--stands for chemical ionization; PA1 EI--stands for electron impact; PA1 HOBT--stands for 1-hydroxybenzotriazole; PA1 EDCI--stands for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; PA1 LC/MS--stands for liquid chromatography/mass spectrometry; PA1 TFA--stands for trifluroacetic acid; PA1 Tr--stands for trityl; and PA1 LRMS--stands for low resolution mass spectrometry.
(1) H; PA2 (2) C.sub.1 to C.sub.6 alkyl; and PA2 (3) --(CH.sub.2).sub.q --R.sup.6 wherein q is an integer of: 1 to 7, and R.sup.6 is selected from the group consisting of: phenyl, substituted phenyl, --OR.sup.7, --C(O)OR.sup.7, --C(O)R.sup.7, --OC(O)R.sup.7, --C(O)NR.sup.7 R.sup.8, CN and --SR.sup.7 wherein R.sup.7 and R.sup.8 are as defined below, and wherein the substituents on said substituted phenyl are each independently selected from the group consisting of: --OH, --O--(C.sub.1 to C.sub.6)alkyl, halogen, C.sub.1 to C.sub.6 alkyl, --CF.sub.3, --CN, and --NO.sub.2, and wherein said substituted phenyl contains from 1 to 3 substituents; PA2 (1) H; PA2 (2) C.sub.1 to C.sub.20 alkyl; PA2 (3) C.sub.3 to C.sub.6 cycloalkyl; PA2 (4) --C(O)OR.sup.7 '; wherein R.sup.7 ' is the same as R.sup.7 defined below except that R.sup.7 ' is not H; PA2 (5) --C(O)R.sup.7 ; PA2 (6) --C(O)NR.sup.7 R.sup.8 ; PA2 (7) allyl; PA2 (8) propargyl; and PA2 (9) --(CH.sub.2).sub.q --R.sup.6, wherein q and R.sup.6 are as defined above, and when q is equal to 1, then R.sup.6 is not OH or SH;
These two latter documents claim the use of the compounds for treatment of allergy and other disorders.
EP 0 428 434 A2 as well as WO 96/29315 and WO 95/06037 describe a wide range of compounds and claim their use as H.sub.3 receptor (ant)agonist. The above documents also include a comprehensive summary of the art dealing with this chemical field.
U.S. application Ser. No. 08/689951 filed Aug. 16, 1996 and U.S. application Ser. No. 08/909319 filed Aug. 14, 1997 disclose compositions for the treatment of the symptoms of allergic rhinitis using a combination of at least one histamine H.sub.1 receptor antagonist and at least one histamine H.sub.3 receptor antagonist.
In view of the art's interest in compounds which affect the H.sub.3 receptors, novel compounds having antagonist activity on H.sub.3 receptors would be a welcome contribution to the art. This invention provides just such a contribution by providing novel compounds having H.sub.3 antagonist activity.